This project will identify genetic factors that predict individual resilience to cognitive impairment arising from Alzheimer's disease (AD) or cerebrovascular disease. At autopsy, approximately 30% of cognitively normal individuals have the pathological features of AD or cerebrovascular disease. Yet, to date very little research has focused on the genetic factors that might contribute to such resilience. The objective of this project is to delineate the genetic architecture of asymptomatic AD. The identification of such novel genes will provide targets for clinical intervention aimed at activating natural biological defenses to neuropathology. This work will apply an innovative method to calculate predicted-gene-expression levels rather than relying solely on genome-wide association study (GWAS) analyses. I will also leverage 2 autopsy datasets: the National Alzheimer's Coordinating Center (n=882) and the Religious Orders Study/Memory and Aging Project (n=954). My mentorship team has extensive experience with these datasets and will provide expert guidance through the research methods and parallel training plan. My central hypothesis is that genetic effects will predict cognitive resilience to the damaging effects of AD and cerebrovascular pathologies. Based on this hypothesis, the primary aims of this application will identify and replicate genetic effects that (1) predict cognitive resilience to AD pathology, and (2) predict cognitive resilience to cerebrovascular pathology. The complementary training plan will equip me with the skills necessary to build out an independent research career focused on genetic resilience by emphasizing the following training content areas: (1) neuropathology, (2) advanced bioinformatics to bridge the gap from genotype to gene expression, and (3) the clinical characterization of AD and vascular dementia. The mentor team is made up of experts in each of these content areas. Their expert training will be augmented by the interdisciplinary training program at the Vanderbilt Memory and Alzheimer's Center, and the cutting edge computational and genomic resources available at Vanderbilt University Medical Center. Together, these practical and intellectual resources provide the ideal training environment. My primary mentor, Dr. Angela Jefferson, has a strong funding history and all the financial and intellectual resources needed to support my transition to independence. These extensive resources will allow me to dedicate 100% protected effort as an Assistant Professor to focus on research and career development. This will ensure that I am fully prepared to compete for independent funding (R01) over the course of the proposed award period.